The functional properties of hemoglobin in solution are being examined in order to derive plausible physical-chemical descriptions of these properties and to correlate the results with the in vivo oxygen uptake properties of intact red blood cells. The cooperative interaction of hemoglobin with ligands is being examined in terms of: (1) the effects of ligand size and stereochemistry; (2) the effects of iron coordination geometry and spin state; (3) effects of protein modification; and (4) the effects of intrinsic differences between the alpha and beta chains. The rates of ligand uptake by intact red cells, resealed erythrocyte membrane preparations, and artificial phospholipid bilayer vesicles are being measured by dual wavelength stopped-flow kinetic techniques. The objective of this study is to assess the importance of membrane diffusion resistance, hemoglobin concentration and modification, and solvent accessibility on the oxygen transport capacities of intact erythrocytes.